Cocaine has the following formula: ##STR1## The basic ring structure of cocaine is a tropane ring system. Thus, in preparing cocaine analogs, this tropane ring system must be preserved.
The illicit use of cocaine represents the one of the most significant problems of drug abuse in modern society. In the United States, researchers estimate that at least 20 million people have used this drug at some point in their lifetimes. One of the biggest problems with cocaine use is its high addictive liability. Cocaine is a potent activator of brain reward systems, and people who take the drug are generally highly motivated to maintain the same effect.
The mechanism of cocaine action involves its ability to block dopamine uptake into neurons by inhibiting the neuronal dopamine transporter. This uptake process is one of the most important ways in which dopamine actions are normally terminated in the central nervous system Thus, administration of cocaine acts to increase dopamine levels, especially in those areas of the brain which activate reward (or pleasure) centers. By measuring the affinity of cocaine analogs in binding to brain dopamine transporters in brain membranes, researchers have been able to predict the relative potencies of these analogs in producing cocaine-like behavioral actions, see Ritz, M. C. and Kuhar, M. J.: J. Pharmacol, Exp. Ther. 248, 1010-1017 (1989). Another important pharmacological characteristic of cocaine is its rapid kinetic properties. Cocaine has an extremely rapid onset of action, and its CNS effects are quickly finished. There is no question that these rapid kinetics contribute to the high incidence of repetitive use of cocaine (e.g., "binges") which are common among addicts.
Despite the advances in understanding cocaine actions, there is as yet no pharmacological strategy that has been effective in treating cocaine addicts. Historically, in the field of drug abuse, there have been three general strategies employed to decrease drug self-administration. It is important to consider how the synthesis of novel cocaine analogs would fit in with these general approaches.
The first approach is replacement drugs. In this strategy, an analog which produces the same effect as the abused drug is given to the addict as a safer alternative. A classic example is methadone maintenance for heroin addicts. By providing an orally-acting drug which replaces heroin, this program seeks to eliminate the problems of intravenous drug use. Synthesis of novel cocaine analogs may be relevant in this approach in at least two different ways. First, compounds which are active orally may be developed. Second, analogs may be developed which are metabolically stable but with slower kinetics of action. Such analogs would be useful in the initial stages of treatment of cocaine addiction, where an analog may substitute for cocaine and thus reduce craving, but act slow enough not to produce the "rush" of euphoria that is such an important component in cocaine addiction.
The second approach is antagonist drugs. In this approach, analogs which actually block the effects of the abused drug are given to the addict. An example is the use of naloxone as an opioid antagonist. Naloxone is especially useful in the treatment of heroin overdose, where it can specifically block the lethal effect of heroin or morphine. In the case of cocaine, however, it is difficult to devise a chemical strategy for producing specific antagonists for at least two reasons. First, little is known about the structure of the cocaine binding site. Therefore, it is imperative that a more complete knowledge of cocaine structure-activity relationships can be obtained so that rational pharmacology can begin to devise effective blocking agents. Synthesis of novel cocaine analogs is vital in establishing this important database. A second reason it is difficult to identify cocaine antagonists is the fact that cocaine binds to the dopamine transporter instead of traditional neurotransmitter receptors. The dopamine transporter is a molecule which acts much more like an enzyme rather than a receptor. Therefore, the chemical strategy for designing drugs to block cocaine at the transporter site is very different than a strategy involving conventional receptors. One potential approach is to synthesize compounds which would act allosterically at the dopamine transporter and thereby modify cocaine binding.
The third approach is punishment drugs In this strategy, an analog is used to produce undesirable side effects of its own when it is taken in conjunction with the abused drug. A well-known example of such a system is disulfuram (Antabuse.RTM.), which produces toxic reactions when taken together with alcohol.
The lack of available significant analogs of cocaine has hampered the significant development of drugs to be used in all three approaches of treatment, namely, replacement drugs, antagonist drugs, and punishment drugs. There is therefore a real and continuing need for the development of a synthesis procedure for cocaine analogs which allow the synthetic chemist to quickly, conveniently and economically develop "tailor made" cocaine analogs. They can then be systematically tested for their suitability as replacement drugs for cocaine, as antagonist drugs for use in cocaine therapy, and for punishment drugs for use in cocaine therapy.
Perhaps the main problem with the original approaches to development of cocaine derivatives as used in the art, see for example Clark, et al., Journal of Medicinal Chemistry, 1973, 16,1260; and Clark, et al., U.S. Pat. No. 3,813,404 issued May 28, 1974, is that this original approach uses as a starting material cocaine itself, which therefore limits synthetic flexibility. There is therefore a continuing need for a broader approach to synthesis of cocaine analogs which enables a wider range of cocaine derivatives to be prepared. In this manner, the molecule of cocaine itself can be explored by varying structural moieties on the molecule and the precise mechanism of cocaine action, including precise knowledge about the structure of the cocaine binding site, can be obtained.
Accordingly, it is a primary object of the present invention to provide a novel synthesis process for cocaine analogs which does not use cocaine as its starting material.
Another primary objective of the present invention is to provide a process for development of cocaine analogs which can be investigated for their use as replacement drugs in cocaine therapy, as antagonist drugs for use in cocaine therapy, and as punishment drugs for use in cocaine therapy.
A still further objective of the present invention is to provide a wide range of cocaine derivatives which can be systematically used and tested for a chemical strategy for producing specific knowledge of the cocaine structure-activity relationship, so that a rational pharmacological approach can be obtained to devising effective blocking agents.
A yet further objective of the present invention is to provide novel pharmacologically active 3-aryltropane derivatives which have potent activity in binding assays substantially higher than known cocaine analogs, thus allowing the compounds to effectively mediate the effect of cocaine by binding to the dopamine transport site in the brain.
The method and manner of accomplishing each of the above objectives, as well as others, will become apparent from the detailed description of the invention which follows hereinafter.